Angiogenic factors in diagnosis, management, and research in preeclampsia.

O bservational studies in humans and experimental studies in animals provide strong evidence that abnormalities in circulating angiogenic factors play a pathogenic role in pre-eclampsia. 1 Numerous angiogenic factor abnormalities have been noted in preeclampsia, but the factors studied most extensively are the antiangiogenic protein, soluble fms-like protein kinase 1 (sFlt1), and the proangiogenic protein, placental growth factor (PlGF). 2 Placental expression of sFlt1 is strikingly increased in preeclampsia, and this is associated with increased levels of maternal circulating sFlt1 and decreased levels of free bioactive PlGF, 3 a finding confirmed by several groups. 1 Alterations in these angiogenic factors occur before clinical signs and symptoms and correlate with the severity of the disease and adverse maternal/neonatal outcomes. 4–7 In addition, basal sFlt1 levels are higher in women with multiple gestation, trisomy 13, and molar pregnancy conditions associated with higher preeclampsia rates. 1 Other synergistic anti-angiogenic proteins such as soluble endoglin have also been demonstrated to contribute to preeclampsia. 8 It has therefore been hypothesized that excessive production of both antian-giogenic proteins sFlt1 (inhibiting vascular endothelial growth factor and PlGF signaling) and soluble endoglin (inhibiting transforming growth factor-β signaling) may lead to endothe-lial dysfunction, and the manifestations of human preeclamp-sia, and that phenotypic preeclampsia is attributable to an antiangiogenic state. During the last decade, several clinical studies were designed to determine potential of angiogenic factors as prediction tests in preeclampsia. However, their accuracy fell far short of sensitivities and likelihood ratios required for clinical use, 17–19 although prediction was much more reliable for early-onset (<34 weeks) preeclampsia. The modest results were interpreted by some as evidence that pre-eclampsia is a heterogeneous disease with no single pathway to explain its spectrum 24 and led to a decreased interest in the importance of these measurements. However, important new roles in diagnoses, and prognosis, plus their potential regarding developing novel treatments, and improving classification schema for more meaningful immediate and remote follow-up investigations have recently emerged. 1,6,25 Here, we explore dilemmas that compromise many preeclampsia studies, discuss potentially new exciting uses of these biomarkers to guide clinical care, and postulate that analysis of angiogenic profiles by improving classification will lead to better studies, particularly those designed to clarify the natural history and remote prognosis of the disorder. Substantial resources have been allocated to preeclampsia prediction studies. In most of these studies, however, the diagnostic criteria are imprecise, few using adverse outcomes other than …